1. The Field of the Invention
The present invention relates to topiramate analogs for use as immunodiagnostic reagents. More particularly, the present invention relates to topiramate analogs, immunogens and antigens prepared from topiramate analogs, antibodies prepared from topiramate-based immunogens, and methods of making and using the same.
2. The Related Technology
Topiramate is chemically represented as 2,3:4,5-bis-O-(1-methyl-ethyliden-βD-fructopyranose sulfamate or 2,3:4,5-di-O-isopropylidene-beta-D-fructopyranose sulfamate, which is shown below. Topiramate is an anti-epileptic drug (“AED”), and is chemically unrelated to many existing AEDs. Topiramate, which is the active ingredient in TOPAMAX®, was approved by the FDA in 1996 for use as adjunctive therapy in the treatment of adults with partial seizures with or without secondary generalization, and may also be useful for Lennox-Gastaut syndrome and infantile spasms.

It is well known that various drugs, such as AEDs, can have different pharmacokinetic and/or pharmacodynamic profiles in different patient populations, which result in the therapeutic drug monitoring (“TDM”) of AEDs to be vitally important. One goal of a TDM program is to optimize a patient's clinical outcome by managing and/or optimizing a medication regimen with the assistance of determining drug concentrations at various times after administration. Accordingly, the drug dose and regimen can be modulated for a single patient or patient population based on TDM.
Several characteristics of topiramate suggest there is a clinical need to individualize patient therapy by use of TDM. It has been suggested that there are large inter-individual variations in dose versus serum concentrations in patients. Also, pharmacokinetic variability plays a major role in the topiramate dosage requirements that are needed to achieve optimum serum concentrations.
It as been suggested that an appropriate range of optimal serum concentrations for topiramate would be 7 to 24 μmol/L in patients receiving a topiramate dose of 125 to 400 mg in addition to other AEDs. Some patients receiving considerably higher doses, which can be up to 2000 mg, had systemic topiramate concentrations as high as 80 μmol/L. Effective TDM can be used to predict dosing regimens that can obtain appropriate topiramate concentrations within the therapeutic index.
Additionally, dose escalation add-on studies have been performed with topiramate with the intention of proceeding to monotherapy where possible. Accordingly, morning serum topiramate concentrations were taken and related to seizure control and associated side effects. Results indicated a clear improvement in seizure control with serum topiramate concentration in the range of 15 to 75 μmol/L, but a reduction in seizure control was seen at serum concentrations greater than 75 μmol/L. Also, there was a significant increase in side effects with serum concentrations greater then 60 μmol/L. Thus, a tentative target serum concentration range for topiramate of about 15 to 60 μmol/L has been suggested; however, most patients can have serum concentrations in the low to mid range with an appropriate dose regimen.
Many methods have been described for determining the systemic concentration of topiramate in a patient. See, Berry D J, et al. Ther Drug Monit; 22:460-4 (2000). Capillary gas chromatographic methods have described the determination of topiramate in serum using flame-ionizing detection and nitrogen-specific detection. See, Holland et al., J Chromatogr; 433:276-281 (1988), and Riffits et al., J Pharm Biomed Anal; 19:363-371 (1999), Tang et al., Ther Drug Monitoring; 22:195-201 (2000). Additionally, methods for using GLC or HPLC with MS have been shown to measure topiramate concentrations. See, Mozayani A, et al. J Anal Toxicol; 23:556-558 (1999), Chen S. et al., J Chromatogr; 761: 133-7 (2001), and Christensen et al., Ther Drug Monitoring; 24:658-664 (2002). However, such methods are impractical for commercial use due to, for example, long sample preparation time, long assay time, high cost, and labor-intensive procedures. Thus, a simple and fast analytical method for measuring topiramate plasma levels is needed for effective TDM.
Topiramate can be measured in plasma or serum using a commercially available (Seradyn, Inc.) FPIA immunoassay. See, U.S. Pat. No. 5,952,187, which is included herein by reference. While the current FPIA immunoassay is simple and fast, the immunoassay is limited by poor availability of previous topiramate analogs and poor user functionality.
Immunoassay techniques have been developed to detect various drugs in biological samples and are well suited for such commercial analytical applications. Accordingly, immunoassays can be used to quickly determine the amount of a drug and/or drug metabolite in a patient's blood. Examples of immunoassays can include, but not limited to, homogeneous microparticle immunoassay (e.g., immunoturbidimetric), or quantitative microsphere systems (“QMS®”), fluorescence polarization immunoassay (“FPIA”), cloned enzyme donor immunoassay (“CEDIA”), chemiluminescent microparticle immunoassay (“CMIA”), and the like.
Accordingly, it would be advantageous to have immunoassays configured to detect topiramate in a patient's blood, serum, plasma, and/or other biological fluids or samples. Additionally, it would be advantageous to have topiramate analogs for use in such immunoassays, and/or topiramate analog-based immunogens for use in producing anti-topiramate antibodies.